Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, discovery of probes/drugs for 7TMRs is an important goal of biomedical research. We use high throughput screening (HTS) and chemical modification to develop small molecule ligands (SMLs) for TSH receptors (TSH-R) and TRH receptors (TRH-R). During this year, we continued our development of these SMLs. 1) We previously reported on a SML agonist for TSH-R that could be used in an animal model to stimulate an increase in radioactive iodine uptake by the thyroid gland and in thyroid hormone secretion after oral administration. We had recognized that the SML was a racemic mixture of two enantiomers. We now have shown that the two enantiomers can be separated and that they exhibit different potencies in vitro and, more importantly, that one is far more effective than the other in vivo. 2) In preliminary studies, it was shown that TRH itself when administered orally to patients with cancer-related fatigue alleviated some of their fatigue symptoms. However, TRH is not a good drug as it is rapidly degraded in the circulation and does not cross the blood brain barrier efficiently. We were intrigued by this observation and with a goal to eventually develop new TRH-R agonists, we decided to develop a mouse model of fatigue to test the activities of new compounds on fatigue. We began by developing a sensitive treadmill test for fatigue-like behavior and showed that it quantitatively measured fatigue-like behavior in mice. We have now used this test to show that a TRH analog, taltirelin, alleviates fatigue-like behavior in mouse models of fatigue induced by cancer burden, chemotherapeutic agents and radiation. (Of note, taltirelin has been used to treat a neurologic disorder in Japanese patients for more than fifteen years.) We think these findings will serve as the pre-clinical data needed to obtain an Investigational New Drug agreement from the USA Food and Drug Administration.